1. Field of the Invention
This invention relates to methods and compositions for treating male impotence and erectile dysfunction.
2. Description of the Prior Art
The process of erection is generally a selective vasodilation of the spongy penile tissue and corpus cavemosum and reductions in outflow, leading to blood pooling, elevation of intra-cavernous pressure, and therefore erection.
Conventional pharmaceutical therapies for impotence or erectile dysfunction primarily include local administration of vascular smooth muscle relaxants, for example papaverine or prostaglandin E1, or .alpha.-adrenoceptor antagonists, such a phentolamine, resulting in penile erection because of an increase in arterial inflow of blood, distension of sinusoids and possible restriction of venous outflow. Thus, intracavernous injection of vasoactive drugs offers impotent patients a form of therapeutic management, and allows one of the tests for differential diagnosis between vasculogenic and other etiologic forms of impotence. Papaverine and prostaglandin E1 are also used in the assessment of pharmacological response of penile erectile tissues under experimental conditions (see Chen et al., J. Urol., 147:1124-1128, 1992).
Other pharmaceutical treatments for impotence have been practiced in the prior art. These include systemic administration of male hormonal preparations such as methyltestosterone and testosterone esters, as well as administration of various naturally occurring plant extracts believed to have aphrodisiac properties, such as yohimbine, ginseng, strychnine and the like. Non-pharmacological therapeutic modalities for impotence include the surgical implantation of penile prostheses and the use of tourniquetlike devices which fit tightly around the shaft of the penis and restrict the flow of blood through the surface veins and the deeper dorsal vein to prolong erection.
All of the foregoing prior art treatment methods suffer from obvious and serious disadvantages. The injection of papaverine and other vasoactive drugs meets with variable success and variable duration of response, and repeated injections into the penis can be painful and traumatic. In some patients these agents cause priapism (undesirable sustained erection), which can lead to structural damage to the organ. The administration of methyltestosterone or testosterone esters may cause toxic effects or inhibit endogenous testosterone formation and spermatogenesis. Orally administered aphrodisiac substances are of marginal and erratic efficacy, and some have significant adverse side effects. The use of surgical implants or toumiquet-like devices can lead to serious problems of infection and trauma, and cause discomfort to both male and female partners.
Several recent studies have shown the obligatory role of nitric oxide for the erection process (see for example Rajfer et al., N. Eng. J. Med., 326:90-94, 1992). Rajfer has concluded that stimulation of the local nerve leads to the production of NO, which increases blood flow in the penile arteries and relaxes the cavernous spaces. When these cavernous spaces are filled they compress venous egress from the corpus cavernosum, leading to an erectile response. Administration of exogenous NO donors may therefore be useful for promoting erections. Several patents have issued regarding the use of nitroglycerin (NTG) and linsidomine applied topically or via intracavernosal injection to treat impotence and erectile dysfunction.
It has been well established that NTG causes relaxation of penile smooth muscle and vascular tissue, including cavernosal tissue. Studies using ointment formulations have demonstrated vasodilation and subsequent engorgement. There is however less convincing evidence that NTG given as 2-10% ointment or plaster applied topically would result in an erection sufficient for vaginal penetration. Using 2% NTG ointment, 18/26 patients had increase in circumference and 7/20 patients had a 50% increase in tumescence (Owen et al. J. Urol. 141:546, 1989).
Studies by Cavallini (J. Urol. 146:50, 1991) showed that, using a single blind design, in 51 patients there was an elevation in penile circumference and rigidity with 10% NTG ointment. In other nonblinded studies, NTG plasters applied locally for several hours, resulted in relatively poor responses in 90% of the patients in the laboratory and 60% of patients at home (Meyoff et al. Br. J. Urol. 69:88 1992). In another study, 30% of patients achieved erections sufficient for vaginal penetration at home whereas 71% of patients had some response (Sonksen, Biering-Sorensen, Paraplegia 30:554, 1992). Using NTG patches in a double blind study, the response to active drug was about 81%, whereas it was 19% with placebo (Claes and Baert, Urol. Int. 44:309; 1989). This was based on post test interviews and not patient diaries or questionnaires which would have been more accurate.
Sexual response was tested in only 3 of 5 studies published studies evaluating erectile response to nitrates. Statistical methods were not evaluated in most of the studies and only one trial reported that NTG had a response that was better than papaverine, another vasodilator, or placebo. In many of these trials headaches were a common occurrence and it is unclear what NTG dose is needed or its duration of action. Furthermore, it was shown that many patients will not demonstrate a useful response to NTG. This may occur because of ultrastructural injury to the smooth muscle, failure of veno-occlusion, or direct venodilation on subtunical veins. Other factors that limit the therapeutic potential of NTG include decrease in systemic blood pressure and development of headache.
It has been disclosed in PCT Application Publication WO 96/34583 that certain organic nitrites, particularly dinitrites such as 1,5-pentane dinitrite, are effective in inducing erection even when applied topically to the penis, and are almost devoid of undesirable side effects caused by systemic vasodilation. However, the nitrites have been found to be irritating to dermal tissues and may, therefore, not be suitable for widespread therapeutic use.
Improved pharmaceutical compositions and methods are required for treating impotence while avoiding the adverse effects experienced with prior art treatment modalities.